Olfactory-Cleft Biopsy in Alzheimer's Disease: An Emerging Neuroimmune Window into Preclinical Pathobiology.

Olfactory dysfunction is an early non-cognitive feature of Alzheimer's disease (AD), but smell impairment has traditionally been used mainly as a behavioral marker. This review examines the emerging use of the olfactory cleft as an accessible source of living neuronal, epithelial, progenitor, and immune cells for studying AD pathobiology. Histopathological and patient-derived culture studies have reported amyloid-β, tau, oxidative-stress, mitochondrial, biometal, and transcriptional abnormalities in olfactory tissue. More recent endoscopically guided brush sampling with single-cell profiling has identified activated memory CD8 T-cell states, inflammatory myeloid programs, and neuronal metabolic changes, including in cognitively unimpaired individuals with abnormal cerebrospinal-fluid amyloid biomarkers. These findings support olfactory-cleft sampling as a research platform for investigating early neural-immune changes, but current evidence is based on small, largely cross-sectional cohorts and does not establish disease specificity, causality, or prognostic utility. Longitudinal multicenter studies integrating olfactory-tissue profiling with established fluid, imaging, genetic, cognitive, and olfactory biomarkers are required before clinical translation.